A General Method for the Suzuki-Miyaura Cross-Coupling of Sterically Hindered Aryl Chlorides: Synthesis of Di- and Tri-ortho-substituted Biaryls in 2-Propanol at Room Temperature

Article abstract of DOI:10.1021/ja038631r

The catalytic formation of di- and trisubstituted ortho biaryl junctions has been achieved using a palladacylce pre-catalyst bearing a N-heterocyclic carbene ligand. This transformation is performed at room temperature in technical grade 2-propanol. Copyr

Full text of DOI:10.1021/ja038631r

Published on Web 12/09/2003
A General Method for the Suzuki-Miyaura Cross-Coupling of Sterically
Hindered Aryl Chlorides: Synthesis of Di- and Tri-ortho-substituted Biaryls in
2-Propanol at Room Temperature
Oscar Navarro, Roy A. Kelly, III, and Steven P. Nolan*
Department of Chemistry, UniVersity of New Orleans, New Orleans, Louisiana 70148
Received September 20, 2003; E-mail: snolan@uno.edu
Transition metal-mediated cross-coupling reactions represent an
extremely versatile tool in organic synthesis.1 Reactions leading to
C-C bond formation are often key steps in a wide range of organic
processes ranging from supramolecular chemistry2 to natural product
synthesis.3 Among these, the Suzuki-Miyaura reaction, involving
the coupling of an aryl halide with an organoboron reagent, has
emerged as a favorite.4,5 Palladium-phosphine complexes have
been the most commonly employed catalysts for the Suzuki-
Miyaura reaction.6,7
Some of the challenges associated with cross-coupling reactions
have focused on the use of “unreactive” aryl chlorides as coupling
partners in view of their attractive cost and readily available
diversity.8 Efforts aimed at developing catalytic systems that
perform at mild reaction temperatures in short times using low
catalyst loadings are an ongoing effort. Some progress has been
achieved in this area.7-9 A remaining challenge is to achieve cross
coupling under these optimum conditions for highly hindered biaryl
junctures such as poly-ortho-substituted biaryls.10
Figure 1. NHC-bearing palladacycles.
Table 1. Suzuki-Miyaura Cross-Coupling of Aryl Chlorides with
Phenylboronic Acid
N-Heterocyclic carbenes (NHC)11 and metallacycle scaffolds12
have been used as alternatives to tertiary phosphines in cross-
coupling reactions.11-13 The NHC are sterically demanding ligands
with better σ-donor ability than tertiary phosphines. The metalla-
cycle framework has shown to be quite robust and capable of high
turnover numbers in the Heck reaction.12 We recently reported a
new class of catalysts combining the highly donating and sterically
demanding NHC with the stability imparted by the palladacycle
framework (Figure 1). These catalysts displayed excellent perfor-
mance in aryl amination and R-arylation of ketones using low
catalyst loading.14 We now report the activity of one of these
catalysts, 1, in the Suzuki-Miyaura cross-coupling reaction.
During the course of performing experiments on the catalytic
dehalogenation of aryl chlorides with 1 using technical grade
2-propanol (1.5 mL) as the solvent and NaOtBu as base (1.2 equiv),
we achieved very high yields of dehalogenated product at room
temperature in minutes.15 In view of similarities between both
processes,7a,16 the activity of this catalyst/solvent system was
examined in the Suzuki-Miyaura reaction. To minimize and
hopefully eliminate the undesirable dehalogenation of the aryl
chloride under catalytic conditions, this substrate was slowly added
to the catalytic reaction mixture. In test reactions, using phenyl-
boronic acid as coupling partner, various aryl chlorides (activated
and unactivated) afforded the corresponding biaryl products in very
short reaction times at room temperature in high yields (Table 1).
The use of anhydrous 2-propanol did not lead to improved yields
or shorter reaction times. This is a true testimony to the robustness
of the catalytic species. The phosphine congeners of 1 do not afford
product under these reaction conditions,17 highlighting the need for
the NHC supporting ligand in this transformation.
a GC yield (isolated yield), average of two runs.
mild conditions afford high yields of desired products in short
reaction times (Table 2). A larger-scale experiment (2.5 mmol of
aryl chloride) was carried out for the reaction in entry 4 and afforded
428 mg (87%) of the desired product in 75 min.
To gain insight on the exact mechanism at play in this system,
the organic fragment liberated in the initial activation step of the
catalysis was isolated and fully characterized in reactions involving
1, NaOtBu and 2-propanol. After flash chromatography, 2-(di-
methylamino)-biphenyl was isolated in quantitative yield. When
the base was not added, the palladacycle was recovered intact. This
suggests an activation pathway involving the formation of a
palladacycle hydride species that subsequently undergoes reductive
elimination of the biphenyl moiety (Scheme 1). The [(IPr)Pd]
The present methodology was also successfully tested in reactions
leading to di- and tri-ortho-substituted biaryls. Reactions under these
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J. AM. CHEM. SOC. 2003, 125, 16194-16195
10.1021/ja038631r CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Synthesis of Di- and Tri-ortho-substituted Biaryls
knowledged for generous gifts of chemicals. Drs. Fre´de´ric Naud
and Martin Struder of Solvias AG are acknowledged for the
donation of materials.
Supporting Information Available: Experimental procedures and
characterization of products (PDF). This material is available free of
charge via the Internet at http://pubs.acs.org
References
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a GC yield (isolated yield), average of two runs.
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Scheme 1. Proposed Mechanism for the Activation of 1
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species generated then becomes available for oxidative addition of
aryl chloride and initiates the catalytic cycle.
In summary, we have described a catalytic system that is general
for the Suzuki-Miyaura cross-coupling reaction involving aryl
chlorides and boronic acids at room temperature. Reactions reach
completion in short reaction times. Sterically hindered unactivated
aryl chlorides couple with sterically hindered boronic acids under
these conditions and lead to di- and tri-ortho-substituted biaryls in
high yields. The use of technical grade 2-propanol as solvent makes
this system very attractive in view of its low cost and environmental
friendliness. Studies aimed at elucidating the exact mechanistic
details involved in this transformation are presently being examined
with this and related palladacycles.
(13) For leading references on NHC as ancillary ligands see: (a) Jafarpour,
L.; Grasa, G. A.; Viciu, M. S.; Hillier, A. C.; Nolan, S. P. Chim. Oggi
2001, 7/8, 10-16. (b) Jafarpour, L.; Nolan S. P. AdV. Organomet. Chem.
2000, 46, 181-222. (c) Weskamp, T.; Bohm, V. P. W.; Herrmann, W.
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(14) Viciu, M. S.; Kelly, R. A., III; Stevens, E. D.; Naud, F.; Studer, M.; Nolan,
S. P.; Org. Lett. 2003, 5, 1479-1482.
(15) See Supporting Information.
(16) Viciu, M. S.; Grasa, G. A.; Nolan, S. P. Organometallics 2001, 20, 3607-
3612.
(17) The use of either the bis(norbornyl)hydrophosphine catalyst (commercially
available) or the palladacycle dimer precursor (bis(2′-dimethylaminobi-
phenyl-2-yl-N,C)di-µ-chloro-dipalladium) did not lead to product forma-
tion for the coupling of 4-chlorotoluene and phenylboronic acid in
2-propanol at room temperature.
Acknowledgment. The National Science Foundation is grate-
fully acknowledged for financial support of this work. Lilly
Research Laboratories and the Lonza Group are gratefully ac-
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